Despite many years of investigation by numerous investigators, transcriptional regulatory control remains an intensely investigated and continuously evolving field of research. Transcriptional regulation is dependent not only on transcription factor activation and chromatin remodeling, but also on a host of transcription factor coregulators-coactivators and corepressors. In addition to transcription factor activation and chromatin changes, there is an expanding array of additional modifications that titrate transcriptional regulation for the specific conditions of a particular cell type, organ system, and developmental stage, and such events are likely to be greatly influenced by upstream signaling cascades. Here, we will briefly review the highlights and perspectives of chromatin remodeling and transcription controls as affected by cofactor availability, cellular energy state, relative ratios of reducing equivalents, and upstream signaling. We also present the C-terminal binding protein (CtBP) as a novel nuclear receptor (NR) coregulator, which exemplifies the integration of a number of transcriptional regulatory controls.